Molecular and structural traits of insulin receptor substrate 1/LC3 nuclear structures and their role in autophagy control and tumor cell survival

Adam Lassak, Mathew Dean, Dorota Wyczechowsk, Anna Wilk, Luis Marrero, Jimena Trillo-Tinoco, A. Hamid Boulares, Jann N Sarkaria, Luis Del Valle, Francesca Peruzzi, Augusto Ochoa, Krzysztof Reiss

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Insulin receptor substrate 1 (IRS-1) is a common cytosolic adaptor molecule involved in signal transduction from insulin and insulin-like growth factor I (IGF-I) receptors. IRS-1 can also be found in the nucleus. We report here a new finding of unique IRS-1 nuclear structures, which we observed initially in glioblastoma biopsy specimens and glioblastoma xenografts. These nuclear structures can be reproduced in vitro by the ectopic expression of IRS-1 cDNA cloned in frame with the nuclear localization signal (NLS-IRS-1). In these structures, IRS-1 localizes at the periphery, while the center harbors a key autophagy protein, LC3. These new nuclear structures are highly dynamic, rapidly exchange IRS-1 molecules with the surrounding nucleoplasm, disassemble during mitosis, and require a growth stimulus for their reassembly and maintenance. In tumor cells engineered to express NLS-IRS-1, the IRS-1/LC3 nuclear structures repress autophagy induced by either amino acid starvation or rapamycin treatment. In this process, IRS-1 nuclear structures sequester LC3 inside the nucleus, possibly preventing its cytosolic translocation and the formation of new autophagosomes. This novel mechanism provides a quick and reversible way of inhibiting autophagy, which could counteract autophagy-induced cancer cell death under severe stress, including anticancer therapies.

Original languageEnglish (US)
Article numbere00608
JournalMolecular and Cellular Biology
Volume38
Issue number10
DOIs
StatePublished - May 1 2018

Keywords

  • Autophagy
  • Cellular distribution
  • Fluorescence recovery after photobleaching
  • Glioblastoma
  • Multiprotein complexes
  • Nuclear suborganelle
  • Phase transition
  • Protein binding
  • Signal transduction

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Lassak, A., Dean, M., Wyczechowsk, D., Wilk, A., Marrero, L., Trillo-Tinoco, J., Hamid Boulares, A., Sarkaria, J. N., Valle, L. D., Peruzzi, F., Ochoa, A., & Reiss, K. (2018). Molecular and structural traits of insulin receptor substrate 1/LC3 nuclear structures and their role in autophagy control and tumor cell survival. Molecular and Cellular Biology, 38(10), [e00608]. https://doi.org/10.1128/MCB.00608-17